The steroid xenobiotic receptor (SXR) is a ligand-dependent transcription factor responsible for the metabolism of foreign compounds in the cell. Activation of SXR by chemotherapeutic agents induces the production of cytochrome enzymes, which oxidatively degrade these agents, and efflux pumps which remove them from the cell. The activation of SXR requires the use of both a ligand and the coactivator peptide SRC-1. This proposal outlines experiments aimed at analyzing the activation of SXR through coactivator peptide interactions. Solid phase combinatorial peptide synthesis will quickly provide us with a wide variety of small compounds with the objective of antagonizing the SXR-SRC-1 interaction and blocking the degradation and expulsion of chemotherapeutic agents. Hydrophobic cross-links within the small peptides will confer them helicity, stability toward proteolytic degradation, and membrane permeability. The binding properties of the peptides will be studied by time-resolved FRET in vitro. The in vivo effects will be examined by luciferase transcription assays. This research will provide a novel way of investigating the problem of drug resistance in cancer cells. Moreover, it will give further insight into the role of coactivator peptides in the activation of a specific gene in a particular cell type.